Post-Replication Repair (PRR) in Saccharomyces cerevisiae : a Systems Biology approach

During the last decade, the DNA damage avoidance pathway called PRR has been extensively characterized. PRR consists of two main sub-pathways: the first one is error-prone and related to Translesion DNA Synthesis (TLS), while the second is error-free and acts through template switching mechanism. The choice between these two sub-pathways is realized through the covalent modifications of PCNA which acts as a molecular switch between the two PRR branches. PCNA mono-ubiquitination directs PRR to TLS, while K63-linked poly-ubiquitination favors the error-free sub-pathway. However, the balance between the two PRR branches as a function of the number of UV-induced lesions and the speed of their bypass has not been determined so far. In this context, mathematical modelling of PRR may represent a useful method to better understand the cellular response after UV damage. Our research is currently focused on the characterization of PCNA modifications in Saccharomyces cerevisiae, in response to various UV doses. Experimental data have been used to develop a mechanistic model of PRR, whose dynamics is under investigation using stochastic simulation algorithms. As all the events of DNA damage bypass occur inside the nucleus, we have to deal with a relatively small amounts of molecular species and, in these conditions, a stochastic modelling approach can properly account for the intrinsic randomness of the biological phenomena. We expect that these in silico analyses will be useful to determine the limiting factors of PRR, and to predict the cellular behaviour under various perturbing conditions. The mathematical predictions are under experimental validation.